Yuuki Takamura

An Observation Trial Without Surgical Treatment in Patients with Papillary Microcarcinoma of the Thyroid

The recent prevalence of ultrasound-guided fine-needle aspiration biopsy has resulted in a marked increase in the number of patients with papillary microcarcinoma (maximum diameter, </= 10 mm) of the thyroid detected by this sophisticated tool. On the other hand, it is debatable whether patients with papillary microcarcinoma should always undergo surgery after diagnosis, because a high incidence of occult papillary carcinoma has been observed in autopsy studies. Thus, we proposed observation without surgical therapy as a treatment option in 732 patients diagnosed with papillary microcarcinoma by the above technique from 1993 to 2001. One hundred sixty-two patients chose observation and were classified as the observation group. During the follow-up period for patients in the observation group, more than 70% of tumors either did not change or decreased in size compared to their initial size at diagnosis. They enlarged by more than 10 mm in 10.2%, and lymph node metastasis in the lateral compartments appeared in only 1.2% of patients during follow-up. On the other hand, 570 patients chose surgical treatment at diagnosis and 56 patients in the observation group who underwent surgery after a period of follow-up were classified as the surgical treatment group. Of these 626 patients, lymph node dissection was performed in 594 patients, and metastasis was confirmed histologically in 50.5%. Multiple tumor formation was seen in 42.8% of patients. In this group, the rate of recurrence was 2.7% at 5 years and 5.0% at 8 years after surgery. Our preliminary data suggest that papillary microcarcinomas do not frequently become clinically apparent, and that patients can choose observation while their tumors are not progressing, although they are pathologically multifocal and involve lymph nodes in high incidence.

Clinical Significance of Metastasis to the Central Compartment from Papillary Microcarcinoma of the Thyroid

We previously demonstrated that for papillary microcarcinoma (PMC), (1) patients with lateral lymph node metastasis detected on preoperative ultrasonography (US) are more likely to develop recurrence, and (2) dissection of the lateral compartment does not improve the prognosis of patients without US-detectable lateral metastasis. In this study, we focused on metastasis from PMC to the central compartment. We investigated the clinical significance of lymph nodes in the central compartment using the same series of 600 patients as used in the previous study. Ultrasound-diagnosed central node metastasis could be found in 30 patients (20.0%). Although the specificity of US for detecting central node metastasis was 99.1%, sensitivity was only 10.9%. Neither US-diagnosed nor pathologically confirmed central node metastasis affected the disease-free survival (DFS) rate of PMC patients. Furthermore, in cases where PMC was located only in one lobe, central node dissection in the contralateral lobe did not improve the DFS rate. These findings suggest that, for PMC, (1) US is an insensitive technique for detecting the central node metastasis, (2) the presence of central node metastasis is unrelated to DFS of patients, and (3) when performing lobectomy for PMC involving only one lobe, dissection of the central compartment in the contralateral lobe is optional.

Papillary Microcarcinoma of the Thyroid: How Should It Be Treated?

We previously demonstrated that (1) most papillary microcarcinomas can be followed without surgical treatment and (2) when surgery is performed, patients with lateral lymph node metastasis detected on preoperative ultrasonography (US) are more likely to develop recurrence. In this study, we further investigated the application of these strategies. To date, we have observed 211 patients (average follow-up 47.9 months). In more than 70% of these patients the tumor size did not increase during the follow-up period. There were no clinicopathologic features linked to tumor enlargement except in tumors ≥ 7 mm, which tended to enlarge in patients followed for 4 years. To evaluate not only whether observation can continue but also how to dissect the lymph nodes optimally at surgery, US diagnosis for lateral node metastasis is essential because the presence of US-diagnosed lateral metastasis is an even stronger predictive marker for recurrence than the presence of pathologically confirmed node metastasis. The positive predictive value (PPV) was 80.6% for US but reached 100% if fine-needle aspiration biopsy (FNAB) of nodes or FNAB-thyroglobulin measurement is added. Furthermore, carcinomas occupying the upper region of the thyroid more frequently showed US-diagnosed and pathologically confirmed lateral metastasis, and those measuring ≥ 7 mm were more likely to show pathologically confirmed lateral metastasis. These findings suggest that, for papillary microcarcinoma: (1) US-diagnosed lateral metastasis is a strong marker predicting a worse relapse-free survival; (2) FNAB of nodes and FNAB-thyroglobulin measurement are useful tools for evaluating lymph node metastasis; and (3) careful US evaluation for lateral metastasis is necessary in patients with a tumor measuring ≥ 7 mm or that is located in the upper region of the thyroid both during observation and preoperatively.

Risk Factors for Recurrence to the Lymph Node in Papillary Thyroid Carcinoma Patients without Preoperatively Detectable Lateral Node Metastasis: Validity of Prophylactic Modified Radical Neck Dissection

BackgroundAlthough papillary carcinoma usually shows mild characteristics, it metastasizes and shows recurrence to the lymph node in high incidences. Of the two representative lymph node compartments to which papillary carcinoma metastasizes, the central compartment can be routinely dissected via the surgical incision made for thyroidectomy. However, the routine application of prophylactic lateral node dissection (modified radical neck dissection [MND]) remains controversial. In this study, we investigated risk factors for lymph node recurrence of papillary carcinoma to determine the appropriate application of prophylactic MND.MethodsWe investigated risk factors for lymph node recurrence in 1,231 patients without preoperatively detectable lateral node metastasis who underwent thyroidectomy, central node dissection, and prophylactic MND for papillary carcinoma between 1987 and 1995.ResultsThe incidence of lateral node metastasis and the number of metastatic lateral nodes significantly increased with carcinoma size. The lymph node disease-free survival (LN-DFS) was also significantly worse in carcinoma with a maximal diameter greater than 3 cm. Massive extrathyroid extension, male gender, and age 55 years or older also reflected a poorer LN-DFS. The 10-year LN-DFS rates of patients with carcinoma having two and three or four of these features were low at 88.5% and 64.7%, respectively, although the rates of those with carcinoma having no or only one characteristic were better than 95%.ConclusionsProphylactic MND is recommended for cases of papillary carcinoma demonstrating two or more of the following four characteristics; male gender, age 55 years or older, maximal tumor diameter larger than 3 cm, and massive extrathyroid extension.

Prognostic Significance of Extrathyroid Extension of Papillary Thyroid Carcinoma: Massive but Not Minimal Extension Affects the Relapse-free Survival

ObjectivesExtrathyroid extension has been recognized as a prognostic factor in papillary thyroid carcinoma. In the most recent version of the UICC TNM classification system, extrathyroid extension has been classified into two grades, minimal extension (extension to sternothyroid muscle or perithyroid soft tissues) and massive extension (extension to subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve). In this study, we investigated the prognostic significance of each of the two types of extension.Patients and MethodsOne thousand and sixty-seven patients with papillary thyroid carcinoma without distant metastasis at surgery, who underwent surgical treatment in Kuma hospital between 1990 and 1995 and had been followed postoperatively for 60 months or more, were enrolled in this study. The grading of extrathyroid extension was based on both pathological findings and intraoperative surgical findings.ResultsIn univariate analysis, although patients with massive extension showed a significantly worse relapse-free survival (RFS) rate than those with no or minimal extension (P < 0.0001), there was no difference in the RFS rate between patients with no extension and those with minimal extension. Among patients with massive extension, the RFS rate tended to be worse in those with posterior extension than in those with anterior extension (P = 0.0562). Furthermore, the RFS rate of patients with massive posterior extension only to the recurrent nerve demonstrated a better RFS rate than those with extension to other posterior organs (P = 0.0052). Multivariate analysis demonstrated that massive extrathyroid extension is recognized as an independent prognostic factor for RFS (P = 0.0003).ConclusionsThese findings suggest that (1) upgrading of T category for tumors with massive extension is appropriate, whereas that for tumors with only minimal extension is not, and (2) careful surgical treatment and postoperative follow-up are required for tumors with massive extension to posterior organs other than the recurrent laryngeal nerve.

Preoperative ultrasonographic examination for lymph node metastasis: usefulness when designing lymph node dissection for papillary microcarcinoma of the thyroid.

ABSTRACTPapillary microcarcinoma has an excellent prognosis after surgical treatment, but how to dissect the lymph nodes remains an open question. In this study, we investigated whether modified radical neck dissection (MND) affected the lymph node recurrence-free survival (LN-RFS) rate for 590 patients with papillary microcarcinoma and recurrence in the lateral compartment who underwent surgery in our hospital between 1993 and 2001. MND was performed in 316 patients, and metastasis in lateral compartment was preoperatively detected on ultrasonography in 67. These 67 patients showed significantly worse LN-RFS (p = 0.0038) than the remaining 249 patients without preoperatively detectable lateral node metastasis. Of the 523 patients (590 minus the 67 patients) whose lateral node metastasis was not detected preoperatively, 249 underwent MND; the remaining 274 patients did not. There was no significant difference in LN-RFS between these two groups. Our preliminary data suggest that with papillary microcarcinoma: (1) MND is not necessary in patients without lateral node metastasis detected on ultrasonography preoperatively, and (2) patients with preoperatively detected lateral node metastasis are more likely to develop recurrence in the lymph nodes so careful MND should be performed.

Clinical Significance of Lymph Node Metastasis of Thyroid Papillary Carcinoma Located in One Lobe

BackgroundPrevious studies have shown that lymph node metastasis can be of prognostic value. In this study, we investigated the clinical significance of node metastasis focusing on metastasis in the central compartment for patients with papillary carcinoma located in one lobe.Patients and MethodsWe investigated the frequency of lymph node metastasis in 759 patients with papillary carcinoma to determine whether and how such metastasis affects disease-free survival (DFS).ResultsCentral node metastasis was observed in 63% of patients, and the frequency was increased in relation to tumor size. The frequency of lateral node metastasis was 62.0%, which was also directly related to tumor size. On multivariate analysis of cases showing tumor larger than 1 cm, central node metastasis was recognized as an independent prognostic factor of DFS. The frequency of metastasis to the paratracheal nodes contralateral to the tumor was drastically elevated for tumors larger than 1 cm, but metastasis to this region did not independently predict worse DFS.ConclusionCentral node metastasis independently predicts a worse DFS for patients with papillary carcinoma larger than 1 cm.

Ultrasonographically and Anatomopathologically Detectable Node Metastases in the Lateral Compartment as Indicators of Worse Relapse-free Survival in Patients with Papillary Thyroid Carcinoma

The recent prevalence of ultrasonography has made it easier to detect lymph node metastasis in the lateral compartment of patients with thyroid carcinoma. In this study, we investigated the prognostic impact of lateral node metastasis preoperatively detectable by ultrasonography (US) and metastasis diagnosed by pathology examination but not detected on preoperative US [anatomopathologically (AP)-detectable metastasis] in 560 patients with papillary carcinoma >1 cm in diameter, who underwent thyroidectomy with modified radical neck dissection at our hospital. Patients with US-detectable metastasis (US+ patients) showed a significantly worse relapse-free survival (RFS) rate than those with no metastasis (US−/AP− patients) or AP-detectable metastasis (US−/AP+ patients) regardless of tumor size. Furthermore, the RFS of US-/AP+ patients with tumors >2 cm was worse than that of US−/AP− patients with tumors >2 cm or US−/AP+ patients with tumors measuring 1.1–2.0 cm. There was no significant difference in RFS between US−/AP+ and US−/AP− patients with tumors measuring 1.1–2.0 cm. These findings suggest that US-detectable lateral metastasis predicts a worse RFS for patients regardless of tumor size, and AP-detectable metastasis affects the RFS of patients with tumors >2 cm.

Prognostic Impact of Serum Thyroglobulin Doubling-Time Under Thyrotropin Suppression in Patients with Papillary Thyroid Carcinoma Who Underwent Total Thyroidectomy

BACKGROUND Detectable serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy implies unsuccessful surgery, indicating a high risk of recurrence. Serum Tg kinetics in such patients have not been extensively studied. We studied serum Tg kinetics in patients with suppressed serum thyrotropin levels and undetectable anti-Tg antibody to minimize the effects of these factors on Tg values, and evaluated the relationship of prognosis to the serum Tg doubling-time. METHODS Between January 1998 and December 2004, 1515 patients with PTC underwent total thyroidectomy in Kuma Hospital. After excluding patients with other thyroid cancers and those positive tests for anti-Tg antibody, there were 426 patients with 4 or more serum Tg measurements at a time that serum thyrotropin concentrations were <0.1 mIU/L. These patients were selected for the present retrospective study. Tg doubling-time was computed using Tg values measured during routine follow-up. Patients were followed for a mean of 88.1 months and a median of 86.7 months. RESULTS Of the 426 patients, 137 patients had 4 or more measurements that revealed detectable Tg in serum Tg. The Tg doubling-time (DT), calculated using all available data, varied widely, and were grouped into those that were <1 year (17 patients), those that were 1-3 years (21 patients), and those that were ≥ 3 years (30 patients), as well as those with a negative value due to decrease in serum Tg (69 patients). There were also 88 patients who had three or fewer serum Tg measurements that showed detectable Tg levels, as well as 201 patients in whom serum Tg measurements were below the lower limit of detection. In the group of patients with a Tg-DT of <1 year the cause specific survival at 10 years was 50%, and in the group with a Tg-DT of 1-3 years it was 95%. In all other groups it was 100%. Many classical prognostic factors (TNM stage, age, and gender) as well as the Tg-DT were significant indicators of survival by univariate analysis, but Tg-DT remained the only independent predictor by multivariate analysis. Tg-DT was also the only independent predictor of distant metastases and loco-regional recurrence on multivariate analysis. Tg-DT calculated using only the first four data [Tg-DT (first four data)] was also the only independent predictor of survival, distant metastases, and loco-regional recurrence on multivariate analysis. CONCLUSIONS Tg-DT (all data or first four data) is a very strong prognostic predictor superior to the classical prognostic factors in patients with PTC.

Risk Factors Contributing to a Poor Prognosis of Papillary Thyroid Carcinoma: Validity of UICC/AJCC TNM Classification and Stage Grouping

BackgroundIn 2002, the UICC/AJCC TNM classification for papillary thyroid carcinoma was revised. In this study, we examined the validity of this classification system by investigating the predictors of disease-free survival (DFS) and cause-specific survival (CSS) in patients.MethodsWe examined various clinicopathological features, including the component of the TNM classification, for 1,740 patients who underwent initial and curative surgery for papillary carcinoma between 1987 and 1995.ResultsClinical and pathological T4a, clinical N1b in the TNM classification, and patient age were recognized as independent predictors of not only DFS, but also CSS of patients. Tumor size, male gender, and central node metastasis independently affected DFS only. There were 1,005 pathological N1b patients, but pathological N1b did not independently affect either DFS or CSS. Regarding the stage grouping, clinical stage IVA including clinical N1b more clearly affected DFS and CSS than pathological stage IVA including pathological N1b.ConclusionClinical stage grouping was more useful than pathological stage grouping for predicting the prognosis of papillary carcinoma patients possibly because pathological stage overestimates the biological characteristics of many pathological N1b tumors.